Acute kidney injury (AKI) is a common, severe complication of cardiopulmonary bypass (CPB) assisted surgeries, and include coronary artery bypass grafts, valve replacements, aortic aneurisms, and organ transplants. Elderly patients, diabetics, and chronic kidney disease (CKD) patients, have very high risk of developing AKI postoperatively. One million CPB surgeries yearly result in thousands of AKI-related deaths and disabilities involving renal replacement therapy (RRT), cumulatively costing billions. Existing renal markers confirming loss of function (e.g. serum creatinine) in AKI are very late markers (1-3 days) for diagnosis of AKI. Few biomarkers (e.g. NGAL, KIM-1) are commercially available for early prediction of AKI. Early biomarkers and rapid tests predicting the severity of post-CPB AKI will enable patient stratification, earlier therapeutic interventions, and drug development for AKI Recently, we have shown that hepcidin is a small peptide (2.78kD) produced in the liver and excreted in urine and may be a good biomarker for AKI post CPB-assisted surgery. In two 100 patient clinical trials with our collaborators in Australia (NCT00910221;Prowle et al. 2012) and Germany (NCT00672334;Haase-Felietz et al. 2011), plasma and urine samples were taken at baseline, 6hr and 24hr from baseline. In contrast to established biomarkers of AKI, plasma creatinine (pCr) and neutrophil gelatinase-associated lipocalin (NGAL), in both these studies urinary hepcidin (uHep;ng/ml) and uHep adjusted for urine creatinine (uHep/uCr;ng/mg) was inversely correlated with severity of AKI when scored by RIFLE criteria (based on pCr). AKI-free patients had highly elevated levels of uHep and uHep/uCr at 6hr that increased through 24hr. uHep and uHep/uCr increased 3- to 7-fold compared to patients with AKI (P = 0.004, P = 0.002) at 6hr in the German study with a AUC-ROC 0.80;0.88, respectively, for prediction of AKI-free recovery and an AUC-ROC 0.81;0.88, respectively, for prediction of RRT-free recovery. These data support uHep and uHep/uCr as a promising biomarker of AKI-free recovery at 6 hours, much earlier than existing biomarkers such as plasma creatinine, urine output volume, and GFR. However, for a biomarker to be useful for diagnosis of AKI, it must be measured and the data returned to the surgeon and ICU staff quickly as there are few established clinical interventions for AKI. We propose development of a portable, quantitative lateral flow device (LFD) that can rapidly determine urine and plasma hepcidin concentrations rapidly and quantitatively in the ICU. We have recently discovered and characterized two new mouse anti-hepcidin monoclonal antibodies (MAb) in ongoing SBIR research (PA 08- 114;2-R44-DK083843-02). For our last submission we made a prototype hepcidin H1 MAb LFD using a gold- conjugated hepcidin tracer that we ultimately abandoned.
The specific aims for our revised Phase I research and development efforts are, 1). Assess urinary and plasma hepcidin, NGAL, and KIM-1 in 1800 de-identified time-matched samples from a prospective clinical study and perform extensive statistical analysis, and 2) Develop a rapid, quantitative lateral flow device (LFD) suitable for plasma and urine hepcidin and test the new device in the clinical samples from the prospective study to evaluate utility of a hepcidin LFD for post-CPB AKI.

Public Health Relevance

One million Cardiopulmonary Bypass (CPB) surgeries (cardiac grafting, valve replacement, transplants) occur annually and Acute Kidney Injury (AKI) following removal from bypass causes thousands of deaths, longer hospital stays, long-term disabilities, and billions in costs. Current biomarkers cannot predict AKI quickly enough following CPB although new clinical data suggests that urine hepcidin may be a novel, early biomarker of the severity of AKI. Development of a rapid, precise, quantitative lateral flow medical device to measure urine hepcidin in the ICU may allow earlier intervention, novel drugs and therapies to be developed, and valuable clinical benefits to high-risk CPB patients, ultimately saving lives and reducing healthcare costs.